PROJECT SUMMARY/ABSTRACT Schistosomiasis, a waterborne infection that affects approximately 200 million people, persists in some areas despite aggressive control measures, for reasons that are not well understood. Hotspots of schistosomiasis persistence and reemergence have been documented in parts of China and, more recently, sub-Saharan Africa. These hotspots threaten to disrupt global targets for schistosomiasis elimination, and highlight the need to understand the origins of new infections in these areas to improve control strategies. Plausible infection sources include human hosts within a community, other mammalian species, and imported infections via, for example, mobile human hosts. However, the actual contributions of such sources to the sustained transmission of complex macroparasites such as schistosomiasis in areas under control pressure is poorly resolved. Genomic tools offer the potential to discern detailed transmission pathways, even for highly inbred parasites such as schistosomes. The proposed research leverages genomic approaches and longitudinal epidemiological data to identify origins of new infections in transmission hotspots. High-resolution sequencing and analysis methods for Schistosoma japonicum will be used to infer parasite ancestry across generations, allowing identification of hosts that serve as infection sources. Over ten years of longitudinal data from southwest China, and ongoing access to schistosomiasis hotspots will be used to characterize host and village-level characteristics that predict the contribution of distinct hosts and the contributions of parasite import to transmission. Specifically, the three proposed aims will evaluate evidence that high transmission human hosts (superspreaders) serve as sources of new infections (Aim 1), identify the conditions that facilitate the contributions of non-human hosts to infection (Aim 2), and test for and identify if present key pathways of parasite import (Aim 3). The ambitious goals for the control of schistosomiasis and other neglected tropical diseases and the persistence of the disease in transmission hotspots despite control measures highlights the need for new approaches to prevent transmission. By determining the extent to which new infections are coming from human hosts, animal hosts, or movement between villages, it will be possible to fine-tune control efforts to focus on key sources of infection in areas approaching elimination.